4-(4&#39;-amino-3&#39;,5&#39;-dichloro-phenyl)-3-tertiary butyl-oxazolidines

ABSTRACT

wherein R is hydrogen, lower alkyl, lower alkenyl, aryl-lower alkenyl, aryl, heteroaryl, halo-aryl or halo-heteroaryl, AND THEIR NON-TOXIC, PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS; THE COMPOUNDS AS WELL AS THEIR SALTS ARE USEFUL AS BRONCHOLYTICS. Compounds of the formula

United States Patent 1 1 1111 3,896,141

Keck et al. July 22, 1975 1 4-(4'-AMINO-3',5'-DlCHLOR0-PHENYL)-3- [57] ABSTRACT Compounds of formula [75} Inventors: Johannes Keck; Gunther Engelhardt, both of Biberach an der Riss, Germany 9 [73] Assignee: Boehringer lngelheim Gmbl-l,

lngelheim am Rhein, Germany [22] Filed: Mar. 8, 1973 [21] Appl. No.: 339,389

[30] Foreign Application Priority Data Mar. 18, 1972 Germany 2213271 [52] US. CL... 260/307 FA; 260/240 D; 260/296 R;

260/570.6; 424/263; 424/272 wherein V 51 Int. Cl C07d 85/26 R is hydrogen, lower alkyl, lower y aryl-lower 58 Field of Search 260/307 FA, 296 R, 240 1) alkenyl, aryl, heteroaryl, halo-aryl or halo-heteroaryl,

[56] References Cit d and their non-toxic, pharmacologically acceptable OTHER PUBLICATIONS acid addition salts; the compounds as well as their Tachikawa et al., CA. 73, 87946s 1970 Salts are useful as bronchdytcs' Primary ExaminerDonald G. Daus Assistant ExaminerR. V. Rush 4 Claims, No Drawings Attorney, Agent, or Firml-lammond & Littell 4-(4'-AMINO-3',5-DlCHLORO-PHENYL)-3 TERTIARY BUTYL-OXAZOLIDINES This invention relates to novel 5-(4'-amino-3',5- dichloro-phenyl)-3-tert.butyl-oxazolidines and their non-toxic, pharmacologically acceptable acid addition salts, as well as to a process for preparing these compounds.

More particularly, the present invention relates to a novel class of compounds of the formula and their non-toxic, pharmacologically acceptable acid addition salts.

The preferred embodiments of substituent R are hydrogen, methyl, ethyl, propyl, isopropyl, n-pentyl, phen-yl, 2-chlorophenyl, pyridyl-(4) and styryl.

The compounds embraced by formula I may be prepared by reacting the compound of the formula OH H I C l CHCH2N CH;, (11

with an aldehyde of the formula R -CHO (lll) wherein R has the same meanings as in formula I. The reaction is advantageously carried out in a solvent, such as ethanol, benzene, toluene or dioxane, under dehydrating conditions, for example, in the presence of anhydrous copper( II) sulfate, at temperatures up to the boiling point of the solvent used, for example, at temperatures between C and 100C. The reaction may also be effected without a solvent; the most preferable way, however, to carry out this reaction is in a reaction vessel provided with a water separator funnel in the presence of a solvent, such as benzene or toluene.

The resulting racemate may, if desired, subsequently be separated into its optically active antipode components, for example, by fractional crystallization of its diastereomeric salt with an optically active acid.

The compounds of the formula I, in both the racemic and optically active form, may be converted into their non-toxic, pharmacologically acceptable acid addition salts in the conventional way. Acids suitable for nontoxic salt formation include, for example, inorganic mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; and organic acids, such as lactic acid, citric acid, maleic acid, 8- chlorotheophylline or the like.

The starting compounds of the formulas l1 and Ill needed for the above-described process are known compounds. 1

The following examples further illustrate the present invention and will enable others skilled in the art to understand it more completely. It should be understood, however, that the invention is not limited solely to the particular examples given below.

EXAMPLE 1 5-(4'-Amino-.3 ,5'-dichlorophenyl )-3-tert.butyloxazol idine and its hydrochloride 27.7 gm (0.1 mol) of 1 -(4-amino-3',5'- dichlorophenyl)-2-tert.butylamino-ethanol were refluxed in 200 ml of benzene with 10 gm (0.13 mol) of an aqueous 40% formaldehyde solution for 5 hours in a vessel provided with a water separator funnel. After 3 hours of refluxing, another 3 gm of said formaldehyde solution were added. The solution was then evaporated, and the residue was reprecipitated from petroleum ether. The base, which had a melting point of 6365C, was dissolved in absolute ethanol, the solution was weakly acidified with ethanolic hydrochloric acid, and the hydrochloride of 5-(4'-amino-3,5- dichlorophenyl)-3-tert.butyl-oxazolidine of the formula which melted at l83l84C (decomp.), was precipitated by the addition of ether.

EXAMPLE 2 5-( 4'-Amino-3-',5 '-dichlorophenyl)-3-tert.buty1-2- methyl-oxazolidine and its hydrochloride were added. Then, the solution was evaporated, the I residue was dissolved in absolute ethanol, and the resulting solution was weakly acidified with ethanolic hydrochloric acid. Ether was added to precipitate the hydrochloride of the formula (in, CH, CH CCH3-HC1 cit--01,

which melted at 178178.5C (decomp).

EXAMPLE 3 4 -Amino-3 ,5 '-dichlorophenyl )-3-tert.butyl-2- phenyl-oxazolidine 10.6 gm (0.1 mol) of benzaldehyde and 18.0 gm (0.065 mol) of l-(4'-amino-3,5-dichlorophenyl)-2- tert.butylamino-ethanol were refluxed in 100 ml of benzene for 30 hours in a vessel equipped with a water separator funnel. Then, the solution was partially evaporated and allowed to stand for some time at +5C, whereby a small amount of unreacted starting compound precipitated out. The precipitate was vacuumfiltered, the filtrate was evaporated and the residue was dissolved in ethanol. 5-(4'-amino-3,5'- dichlorophenyl)-3-tert.butyl-2-phenyl-oxazolidine of the formula (3H, CH

CH CCH,-, O N C a Cl (hails which melted at 92-l 23C, crystallized out in the form of a mixture of the two pairs of diasteroisomers.

EXAMPLE 4 Using a procedure analogous to that described in Example l, 5-(4-amino-3',5'-dichlorophenyl)-3- tert.butyl-2-ethyl-oxazolidine was prepared from l-(4'- amino-3 ',5 '-dichlorophenyl)-2-tert.butyl-aminoethanol and propionaldehyde. The melting point of the hydrochloride was l76l77.5C (decomp.).

EXAMPLE 5 Using a procedure analogous to that described in Example l, 5-(4-amino-3 ',5 '-dichlorophenyl)-3- tert.butyl-2-propyl-oxazolidine was prepared from 1- (4-amino-3, 5'-dichlorophenyl)-2-tert.butyl-aminoethanol andbutyraldehyde. The melting point of the hydrochloride was l74-l75.5C (decomp.).

EXAMPLE 6 Using a procedure analogous to that described in Example l, 5-(4'-amino-3 ',5 '-dichlorophenyl)-3- tert.butyl-2-isopropyl-oxazolidine was prepared from l-(4'-amino-3',5'-dichlorophenyl)-2-tert.butyl-aminoethanol and isobutyraldehyde. The melting point of the hydrochloride was l63166C (decomp.).

EXAMPLE 7 Using a procedure analogous to that described in Example l, 5-(4'-amino-3',5'-dichlorophenyl) 3-tert.butyl-2- n-pentyl-oxazolidine was prepared from 1-(4- amino-3',5'-dichlorophenyl)-2-tert.butyl-aminoethanol and caproaldehyde. The melting point of the hydrochloride was l54155C.

EXAMPLE 8 1 Using a procedure analogous to that described in Ex- 5-(4-amino-3,5-dichlorophenyl)-3- ample 3,

tert.butyl-2-pyridyl-(4)-oxazolidine was prepared 4 from l-(4-amino-3',5' dichlorophenyl)-2tert.butylamino-ethanol and pyridine-4-aldehyde. The product had the formula and melted at l36140C.

EXAMPLE 9 Using a procedure analogous to that described in Example 1, 5-(4'-amino-3',5'-dichlorophenyl)-3- tert.butyl-2-(2-chloro-phenyl)-oxazolidine was prepared from l-(4-amino-3,5-dichlorophenyl)-2-tert- .butyl-amino-ethanol and 2-chloro-benzaldehyde. The compound was precipitated in the form of its hydrochloride of the formula tert.butyl-2-styryl-oxazolidine was prepared from 1- (4'-amino-3,5 dichlorophenyl)-2-tert.butyl-aminoethanol and cinnamaldehyde. The compound was precipitated in the form of its hydrochloride of the formula which melted at 172 174c (decomp.).

5 V The compounds according to the present invention, that is, those embraced by formula .l -abo ve and their nontoxic, phatmacologically acceptable aci'dlad dition salts have useful pharmacodynamicproperties More particularly, the compounds of the instant invention exhibit bronchol'ytic activity in warm-blooded animals, such as guinea pigs, I ,1 .The broncholytic activity of-the compounds of the present inven tion. was ascertained by the standard test method of KonzetgRcissler, Arch. 'exp. -P a th. Pharmakol. 195, 71 (1940 on anesthetized guinea pigs.

Bronchial spasms were artificiallyfindiiced'in the test animals by intravenous administration'of20 y/kg of acetylcholine, the, test compound under investigation was administered intravenously, and the percentage decrease inthe bronchial spasms wasrecorded. The' test was repeated at varying dosage levels of the test compound, theaveraged values were plotte dlon a doseactivity graph, and the median effective broncholytic dose (ED i.e. the dose whichre duces the bronchial spasms by 50 was graphically determined.

The acute toxicity of the compounds being tested was determined or groups of l mice each. The LD i,e. the dose whichcauses the death of 50% of the animals within 7 days, was graphically calculated according to the method of Litchfieldand Wilcoxon.

. Illustrative resultsjof these tests,]a s determined for the following compounds:

A -(4-amino-3,5' dichloro-phenyl)-3-tert.butyloxazolidine hydrochloride, 7 B 5-(4-amino-3',5'-dichloro-phenyl)-3-tert.butyl- 2-methyl-oxazolidine hydrochloride, C 5-(4'-amino-'3',5'-dichloro-phenyl)-3-tert.butyl- 2-ethyl-oxazolidine hydrochloride, D 5-(4'-amino-3,5-dichloro-phenyl)-3-tert.butyl- 2-p ropyl-oxazolidine hydrochloride, E 5-(4-amino-3,5-dichloro-phenyl)-3-tert.butyl- 2-iso-propyl-oxazolidinehydrochloride, F =5-(4-amino-3,5kdichloro-phenyl)-3-tert.butyl- 2-styryl-oxazolidine hydrochloride and G 5-(4'-amino-3',5'-dichloro phenyl)-3-tert.butyl- 2-n-pentyl-oxazolidine hydrochlo 'd'e, are shown in the following table. .2

TABLE Substance ED ry [k'g duration of activity LD mgm/kg i.v in minutes i.v.

A 6.4 120 30.0 p B 5.5 39.8

C "7.2 D 1l.5 5 ,,,,5.4';.,; 35.9 F 26.0 G -.-l3.5

P gredients. in customary. dosage unit composition s,.th at is, compositions in dosage unit form consisting;.essen-,

tially of an inert pharmaceutical,carrier andone effective dosage unit of the active ingredient, suchas tablets,

coated pills, capsules, wafers, powders, solutions, suspensions, emulsions, syrups, suppositories, and the like.

One effective dosage unit of the compounds according to the present invention is from 0.167 to 1.67 y/kg body weight, preferably 0.417 to 0.833 y/kg body weight.

. -6 fhTh e followjngexamples illustrate a few pharmaceuticalidosage unit compositionscomprising a compound offthepresent invention as an active ingredient and represent the best modes contemplated ofputting the in- 5 vention into practical use. The parts are parts by weight unless otherwise specified.

EXAMPLE" 11 Tablets The tablet composition was compounded from the following ingredients:

5-(4'-amino-3',5'-dichlorophenyl)-3- tert.butyl-oxazolidinc hydrochloride 0.05 parts Lactose 82.45 parts 15 Potato starch 33.00 parts Polyvinylpyrrolidone 4.00 parts Magnesium stearate 0.50 parts Total l20.00 parts Preparation:

The active ingredient and-polyvinylpyrrolidone were dissolved-in ethanol. Themlxture of the lactose and the potatostarchwas homogeneously moistened with the active ingredient/granulation solution and passed through a screen of 1.5 mm mesh-size. Subsequently, the mixture was dried at 50C and again passedthrough a screen of. 1.0mm meshsizesThe granulate thusobtained was admixed with the magnesium stearate and compressed into l20.:mgm-tablet s. Each tablet contained 0.05 mgm of the oxazolidine compound and was an oral dosage unit composition with effective broncholytic activity.

EXAMPLE l2 c Coated tablets I The tablet core composition was compounded from the following ingredients: v 7

5-(4-amino-3".5'-dichlorophe'nyl)-3- v V tert.butyl-oxazolidine hydrochloride 0.025 parts 40 Lactose 82.475 parts Potato starch 33.000 parts Polyvinylpyrrolidone 4.000 parts Magnesium stearate m Total 120.000 parts v Preparation:

Using a procedure, analogous to that described in Example. 1 1,, tablet coresweighing l20 rngm eachbwere v prepared. The-tablet cores were coated in known manner withathin shell consisting essentially of a inixture of sugar andtalcum and thenpolished withbeeswax.

Each coated tablet contained0.025 mgm of the oxa'zolidine compound, and was: an oral dosage unit composi- 7 tion with effective broncholytic activity.

' EXAMPLE 13 Gelatin capsules The capsule filler composition was compounded from the following ingredients:

tert. I utyl-oxazolidine hydrochloride 0.025 parts Lactose 59.975 parts Corn starch 60.000 arts Total 120.000 parts Preparation:

The active ingredient was intimately admixed with the lactose and the corn starch, and mgm-portions of the mixture were filled into gelatin capsules of suitable size. Each gelatin capsule contained 0.025 mgm of the oxazolidine compound. and was an oral dosage unit composition with effective broncholytic activity.

EXAMPLE l4 Hypodermic solution The solution was compounded from the following ingredients:

tert.butyl-oxazolidine hydrochloride 002 parts Citric acid 2.50 parts Sodium hydrogen phosphate 750 parts Sodium chloride 4.60 pans Distilled water q.s.ad 2000.00 parts by vol.

Preparation:

EXAM PLE 1 5 Suppositories The suppository composition was compounded from the following ingredients:

5-( 4 '-amino-3 .5 '-dichlorophenyl )-3- tert.butyl-oxazolidine hydrochloride 0.05 parts Suppository base (e.g. cocoa butter) 1669.95 parts Total 1700.00 pans Preparation:

The active ingredient was finely powdered and stirred into the suppository base, which had been melted and cooled to 40C, using an immersion homogenizer. 1700 mgm-portions of the mixture at 37C were poured into cooled suppository molds and allowed to harden therein. Each suppository contained 0.05 mgm of the oxazolidine compound and was a rectal dosage unit composition with effective broncholytic activity.

EXAMPLE l6 Syrup The syrup was compounded from the following ingredients:

tert.butyl-oxazolidine hydrochloride 0.0005 parts Benzoic acid 0.1000 parts Tartaric acid 1.0000

parts Sugar 50.0000 parts Flavoring 1.0000 parts Food coloring 0.0500 parts Distilled water q.s.ad 100.0000 parts by vol.

Preparation:

The benzoic acid, the tartaric acid, the active ingredicm, the food coloring and the sugar were successively dissolved in about 60% of the required amount of distilled water which had been heated to C. After cooling to room temperature, the flavoring was added to the solution, and the composition was diluted with distilled water to the indicated volume and then filtered. Each 5 ml of the resulting syrup contained 0.025 mgm of the oxazolidine compound and was an oral dosage unit composition with effective broncholytic activity.

Analogous results are obtained when any one of the other oxazolidines embraced by formula 1, or a nontoxic, pharmacologically acceptable acid addition salt thereof is substituted for the particular oxazolidine in Examples 1 l to 16. Likewise, the amount of active ingredient in these illustrative examples may be varied to achieve the dosage unit range set forth above, and the amounts and nature of the inert pharmaceutical carrier ingredients may be varied to meet particular requirements.

While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art that the invention is not limited to these particular embodimen'ts, and that various changes and modifications may be made without departing from the spirit of the invention or the scope of the appended claims.

We claim:

1. A compound of the formula :1: CH H C-CH a o N CH 1 1 cl Cl-l---CH HzN able acid addition salt thereof.

l l l l 1 

1. A COMPOUND OF THE FORMULA
 2. A compound of claim 1, which is 5-(4''-amino-3'',5''-dichlorophenyl)-3-tert.butyl-oxazolidine or a non-toxic, pharmacologically acceptable acid addition salt thereof.
 3. A compound of claim 1, which is 5-(4''-amino-3'',5''-dichlorophenyl)-3-tert.butyl-2-methyl-oxazolidine or a non-toxic, pharmacologically acceptable acid addition salt thereof.
 4. A compound of claim 1, which is 5-(4''-amino-3'',5''-dichlorophenyl)-3-tert,butyl-2-isopropyl-oxazolidine or a non-toxic, pharmacologically acceptable acid addition salt thereof. 